First described by Dr. Leo Kanner, autism is a pervasive developmental disorder (PDD) characterized by the presence of limited interests and activities, as well as by impairments in socialization and communication. Despite the fact that there are many suggestions for the causes of this disorder, including, but not limited to, genetics, the environment, and vaccinations, there is no one cause of autism. With the advent of electroencephalography (EEG), observations of aberrant patterns in autistic patients contributed the contemporary understanding of the syndrome as a brain-based disorder. The heterogeneity of the clinical syndrome would seem to indicate that the disorder termed autism may arise from a constellation of different etiologies. For example, about one quarter of autistic patients have comorbid epilepsy. Studies suggest another subgroup, some 40-55% of autistic patients, suffers mental retardation. Furthermore, even though the heritability of autism is relatively high, only some 10% of cases can be attributed to a known genetic aberration.
Although there are diagnostic criteria listed in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), the International Statistical Classification of Diseases and Related Health Problems (ICD-10), the Autism Diagnostic Observation Schedule (ADOS) and the Autism Diagnostic Interview-Revised (ADI-R), the disorder is currently diagnosed solely using core behavioral criteria selected to define autism, typically during the toddler or preschool years at the earliest. There is presently no clinical laboratory test for diagnosing autism. To begin intervention at the earliest possible time, the development of biological quantitative methods to predict the presence or risk of autism is necessary.
Proteolytic cleavage of amyloid precursor protein (APP) by the sequential actions of β- and γ-secretases form the neurotoxic amyloid beta (Aβ) peptide, which typically consists of 40 or 42 amino acid residues (the amyloidogenic pathway). On the other hand the non-amyloidogenic pathway consists of APP cleavage by α-secretase which yields the neurotrophic product, secreted APP-α (sAPP-α). As α-secretase cleaves APP within the Aβ sequence, Aβ formation is subsequently prevented. In a recent report Sokol and colleagues demonstrated, in children with severe autism and aggressive behavior, that serum sAPP-α levels were more than twice that of children without autism and up to four times higher than observed in children with mild autism [see Sokol D K, Chen D, Farlow M R et al. High levels of Alzheimer beta-amyloid precursor protein (APP) in children with severely autistic behavior and aggression. J Child Neurol. 2006; 21(6): 444-9).
Based on the Sokol study, the inventors speculated that sAPP-α is a peripheral biomarker that can be used for the diagnosis of autism. In addition, they developed a sensitive enzyme-linked immunosorbent assay (ELISA) to specifically measure sAPP-α secretion in human plasma and umbilical cord blood and they hypothesize that this ELISA will show a significant difference in sAPP-α levels of autistic patients when compared to healthy individuals. The goal was to design a laboratory tool for early diagnosis of autism. (see Bailey et al. Peripheral biomarkers in Autism: secreted amyloid precursor protein-α as a probable key player in early diagnosis. Int J Clin Exp Med (2008) 1, 338-344).
There are substantial gaps, however, in the knowledge of the neurodevelopmental mechanisms underlying autism which arise largely from the difficulty of characterizing the circuitry subserving higher mental functions, the complexity of the genetic underpinnings of “normal” versus “abnormal” behavioral variation in childhood. Moreover, there is a lack of satisfactory autism animal models. (see Moy S S, Nadler J J. Advances in behavioral genetics: mouse models of autism. Mol Psychiatry. 2008; 13(1): 4-26)). What is needed, therefore, is an experimental animal model which expresses a peripheral biomarker to test target diagnostic and therapeutic agents for autism.